Eva Hernando, PhD
Associate Professor of Pathology
PhD, 2009 University Autonoma Madrid, Spain.
Tumor cell-of-origin, stem cell differentiation, Metastasis
Melanoma, Sarcoma, Metastasis, microRNA
550 First Avenue
Smilow Room 305
New York, NY 10016
Office Tel: (212) 263 9054
Lab Tel: (212) 263-9057
Fax: (212) 263 8211
Traditionally, mature cells in specific tissues and organs have been regarded as the cell-of-origin of the corresponding tumors. However, the observation that tumor cells need to accumulate genetic and phenotypic alterations over extended time periods has turned the view to stem cells or progenitors, which are broadly distributed in local reservoirs. These cells, in charge of maintaining tissue homeostasis, are contemplated as the target of neoplastic transformation.
Our laboratory is investigating the cell-of-origin and the molecular bases of two tumor types: melanoma and sarcoma. We hypothesize that alterations in normal differentiation and tissue homeostasis contribute to tumor initiation, and that the retention or reactivation of stem cell properties contribute to tumor progression and aggressive behavior (i.e., resistance to therapy, metastasis). A limitation for these studies is our partial understanding of the normal differentiation of neural crest (for melanoma) and mesenchymal (for sarcoma) stem cells. To overcome this limitation, we are investigating epigenetic mechanisms, including miRNA-mediated processes that control multipotency and differentiation of stem cells, and might contribute to tumorigenesis when altered.
Role of microRNA in mesenchymal stem cell differentiation and sarcoma
Our laboratory has established and characterized the in vitro differentiation of human Mesenchymal Stem Cells (hMSCs) into smooth-muscle (SMC), the lineage of origin of Leiomyosarcomas (LMS), tumors that appear in the uterus and the retroperitoneum. Using computational analyses, we determined that LMS are more similar to hMSCs than to mature SMCs and myometrium (Danielson et al., Am J Path 2010). Also, we found that some miRNAs down-regulated during hMSC differentiation are overexpressed in uterine LMS compared to normal myometrium. We are currently investigating whether these candidate miRNAs play an active role in SM differentiation in vitro and in vivo and whether their alteration contributes to LMS genesis and/or progression.
Funding:NIAMS/NIH (R21AR062239-01) (PI: Hernando). “Multilineage regulation of mesenchymal stem cell differentiation by microRNAs”.
Role of miRNA in melanoma metastasis
Melanoma is the most aggressive form of skin cancer; it is, in fact, the paradigmatic metastatic tumor. Accumulating evidence suggests that the processes involved in metastasis are closely related to developmental defects. Two lines of evidence that point to such a link are of particular interest to us. First, several studies over the past few years have shown that alterations in microRNA (miRNA) expression, which serve important regulatory functions during development, are crucial in promoting tumorogenicity in different cancers, including melanoma (reviewed in Segura et al., Carcinogenesis 2012). Second, recent work in various cancers has suggested the existence of Cancer Stem Cells (CSC), a sub-population of malignant cells endowed with the capacity to self-renew. Although the idea of melanoma stem cells remains controversial, melanoma cells often express stem cell genes, display multidifferentiation potential, and seem to recapitulate the migratory nature of neural crest stem cells from which melanocytes arise. Our group discovered that the miRNA cluster miR-183-96-182 is frequently overexpressed in melanoma tissues and cell lines, it promotes migration in vitro and metastasis in vivo, and it does so in part by targeting MITF, a master regulator of melanocyte differentiation(Segura et al., PNAS 2009). We found that both human embryonic stem cells (hESCs) and quiescent mouse melanocyte stem cells (mMSCs) express miR-183-96-182 at high levels comparable to those of some melanoma cell lines, while expression of this cluster decreases during in vitro melanocyte differentiation in inverse correlation with MITF levels. Based on these data, we propose that miR-183-96-182 expression is an important part of both normal melanocyte development and melanoma metastasis, and we are investigating if modulation of its expression confers stem cell-like properties onto melanoma cells, thereby promoting the chemoresistant and metastatic behavior of these tumors.
Funding: NCI/NIH (1R01CA155234) (PI: Hernando). “Regulation and role of miR-183-96-182 in melanocyte differentiation and melanoma”. 1R01CA163891-01A1, (PI: Hernando) “Prognostic and Functional Role of microRNAs in Melanoma Brain Metastasis”. DOD Collaborative Award CA093471 (PI: Hernando) “Altered microRNAs in melanoma brain metastasis”.
Role of BET proteins in stem cell maintenance and melanoma.
The bromodomain and extra-terminal domain (BET) proteins regulate acetylation-mediated interactions critical for transcription. We are investigating the role of BET proteins in governing embryonic stem cell (ESC) identity. BET chemical inhibition compromised the ability of ESCs to self-renew and suppressed pluripotency genes expression. These genes seem to display a specific defect in elongation, as assessed by polymerase II profiles and K36-thrymethilation (K36me3). Among BET proteins, Brd4 silencing was able to phenocopy the effects of BET inhibition on ESCs and impaired teratoma formation. We are currently investigating the mechanism(s) by which BET proteins, particularly BRD4, regulate the transcriptional elongation of the pluripotency gene network.
Interestingly, BRD4 was also found significantly upregulated in primary and metastatic melanoma tissues compared to melanocytes and nevi. Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. RNA sequencing of BET inhibitor-treated cells followed by gene ontology analysis showed a striking impact on transcriptional programs controlling cell growth, proliferation, cell-cycle regulation and differentiation. We are currently investigating the mechanism(s) by which BRD4 plays an oncogenic role in melanoma.
Funding: Melanoma Research Alliance Pilot grant. “Novel epigenetic regulators for melanoma therapy”
- M.V. Guijarro MV, Dahiya S, Danielson L, Segura, MF, Vales-Lara FM, Menendez S, Popiolek D, Mittal K, Wei JJ, Pandolfi PP, Cordon-Cardo C, and Hernando E. Dual Pten/p53 suppression promotes sarcoma progression by triggering Notch signaling.Am J Pathol. 182(6):2015-27 (2013) PMID: 23708211
- Segura M, Greenwald H, Hanniford D, Osman I, Hernando E. MicroRNA & cutaneous melanoma: from discovery to prognosis and therapy. Carcinogenesis 33(10):1823-32. (2012). PMID: 22693259
- C. Huynh, L. Poliseno, MF. Segura, R. Medicherla, A. Haimovic, S. Menendez, S. Shang, A. Pavlick, Y. Shao, F. Darvishian, JF. Boylan, I. Osman and E. Hernando. (2011). The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma. PLoS ONE, 6(9): e25264. PMID: 21980408
- A. Gaziel-Sovran, M.F. Segura, R. Di Micco, S. Menendez, JF. Rakus, M.K. Collins, D. Hanniford,, E. Vega-Saenz de Miera, , JF. Dankert, RS. Kerbel, N. Bhardwaj, F. Darvishian, J. Zavadil, A. Erlebacher, LK. Mahal, I. Osman, and E. Hernando. (2011). MiR-30b/30d regulation of GalNAc transferases enhances invasion and synthesis of the immunosuppressive cytokine IL-10 during metastasis. Cancer Cell (20):1-5. PMID: 21741600
- C. Huynh, M.F. Segura, A. Gaziel, S. Menendez, F. Darvishian, L. Chiriboga, B. Levin, D. Meruelo, I. Osman, J. Zavadil, E. G. Marcusson and E. Hernando. (2011). Efficient in vivo microRNA targeting of liver metastasis. Oncogene. 30(12):1481-8. PMID: 21102518
- MF Segura, I Belitskaya-Lévy, AE Rose, J Zakrzewski, A Gaziel, D Hanniford, F Darvishian, I Osman, and E Hernando. (2010). Melanoma MicroRNA signature predicts post-recurrence survival. Clin Can Res 16(5): 1577-1586. PMID: 20179230
- L.S. Danielson, S. Menendez, C. Stephan-Otto Attolini, M.V. Guijarro, M. Bisogna, J.J. Wei, N.D. Socci, D.A. Levine, F. Michorand E. Hernando. (2010). A differentiation-based miRNA signature identifies leiomyosarcomas as a mesenchymal-stem cell related malignancy. Am J Pathol. 177(2):908-17. PMID: 20558575
- A. Kapoor, M.S. Goldberg, L. Cumberland, K. Ratnakumar, M. F. Segura, P.O. Emanuel, S. Menendez, C. Vardabasso, G. LeRoy, C.I. Vidal, D. Polsky, I. Osman, B.A. Garcia, E. Hernando, E. Bernstein. (2010). The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature, 468(7327):1105-9. PMID: 21179167
- MF Segura, D Hanniford, S Menendez, L Reavie, X Zou, S Alvarez-Diaz, J Zakrzewski, E Blochin, A Rose, D Bogunovic, D Polsky, JJ Wei, P Lee, I Belitskaya-Levy,N Bhardwaj, I Osman, and E Hernando. (2009) Aberrant miR-182 expression promotes melanoma metastasis by repressing Foxo3 and MITF. PNAS 106 (6), 1814-1819. PMID: 19188590